Our primary goal is to understand the organization and control of taste signaling i.e. how individual pathways involved in taste transduction function and interact with each other. In the long term, this will involve defining the various components and the organization required for taste responses both peripherally and centrally and will help to elucidate the logic of taste coding. Initially, we would like to know what receptors mediate sweet, sour, salty, umami (savory) and bitter tastes; how tastant specificity and taste discrimination are accomplished; what topographic organization exists in the various taste buds and papillae; and how the information is transmitted and encoded in the afferent nerves. Our focus has been on the isolation and characterization of genes encoding sweet, amino acid and bitter taste receptors and using these to mark the cells, define the corresponding signaling pathways, dissect receptor specificity, generate topographic maps, and trace the respective neuronal connectivity circuits. This work has identified and characterized two families of G-protein coupled receptors, T1Rs and T2Rs, that are expressed in distinct subsets of taste receptor cells and that include functionally validated sweet, amino acid and bitter taste receptors. We have also developed a number of genetically engineered mouse lines that have had a major impact in our understanding of how sweet, bitter and umami taste are encoded at the periphery. In this reporting period we have focused on the role of T2Rs and T2R-expressing cells in bitter taste. Bitter taste detection functions as an important sensory input to warn against the ingestion of toxic and noxious substances. T2Rs are a family of approximately 30 highly divergent G-protein-coupled receptors (GPCRs) that are selectively expressed in the tongue and palate epithelium and are implicated in bitter taste sensing. Using a combination of genetic, behavioral and physiological studies, we demonstrated that T2R receptors are necessary and sufficient for the detection and perception of bitter compounds, and showed that differences in T2Rs between species (human and mouse) determine the selectivity of bitter taste responses. In addition, we showed that mice engineered to express a bitter taste receptor in 'sweet cells' became strongly attracted to its cognate bitter tastants, whereas expression of the same receptor (or even a novel GPCR: a modified opioid receptor) in T2R-expressing cells generated in mice that are averse to the respective compounds. These results illustrate the fundamental principle of bitter taste coding at the periphery: dedicated cells act as broadly tuned bitter sensors that are wired to mediate behavioral aversion. These studies highlight the nature of taste sensation and help establish that the 'taste' of a sweet or a bitter compound (i.e. the perception of sweet and bitter) is a reflection of the selective activation of T1R-expressing versus T2R-expressing cells, rather than a property of the receptors or even the tastant molecules.